Pharmaceutical formulations for dry powder inhalers

ABSTRACT

A powder for use in a dry powder inhaler comprises: i) a fraction n of fine particle size constituted by a mixture of physiologically acceptable excipient and an additive; ii) a fraction of coarse particles; and iii) at least one active ingredient. The powder is suitable for efficacious delivery of active ingredients into the low respiratory tract of patients suffering from pulmonary diseases such as asthma. In particular, the invention provides a formulation to be administered as dry powder for inhalation which is freely flowable, can be produced in a simple way, is physically and chemically stable and capable of delivering accurate doses and/or high fine particle fraction of low strength active ingredients by using a high- or medium resistance device.

The invention relates to a formulation to be administered as dry powderfor inhalation suitable for efficacious delivery of active ingredientsinto the low respiratory tract of patients suffering of pulmonarydiseases such as asthma.

PRIOR ART

Inhalation anti-asthmatics are widely used in the treatment ofreversible airway obstruction, inflammation and hyperresponsiveness.

Presently, the most widely used systems for inhalation therapy are thepressurised metered dose inhalers (MDIs) which use a propellant to expeldroplets containing the pharmaceutical product to the respiratory tract.However, despite their practicality and popularity, MDIs have somedisadvantages:

-   i) droplets leaving the actuator orifice could be large or have an    extremely high velocity resulting in extensive oropharyngeal    deposition to the detriment of the dose which penetrates into the    lungs; the amount of drug which penetrates the bronchial tree may be    further reduced by poor inhalation technique, due to the common    difficulty of the patient to synchronise actuation form the device    with inspiration;-   ii) chlorofluorocarbons (CFCs), such as freons contained as    propellants in MDIs, are disadvantageous on environmental grounds as    they have a proven damaging effect on the atmospheric ozone layer.

Dry powder inhalers (DPIs) constitute a valid alternative to MDIs forthe administration of drugs to airways. The main advantages of DPIs are:

-   i) being breath-actuated delivery systems, they do not require    co-ordination of actuation since release of the drug is dependent on    the patient own inhalation;-   ii) they do not contain propellants acting as environmental hazards;-   iii) the velocity of the delivered particles is the same or lower    than that of the flow of inspired air, so making them more prone to    follow the air flow than the faster moving MDI particles, thereby    reducing upper respiratory tract deposition.

DPIs can be divided into two basic types:

-   i) single dose inhalers, for the administration of pre-subdivided    single doses of the active compound;-   ii) multidose dry powder inhalers (MDPIs), either with    pre-subdivided single doses or pre-loaded with quantities of active    ingredient sufficient for multiple doses; each dose is created by a    metering unit within the inhaler. On the basis of the required    inspiratory flow rates (l/min) which in turn are strictly depending    on their design and mechanical features, DPI's are also divided in:-   i) low-resistance devices (>90 l/min);-   ii) medium-resistance devices (about 60 l/min);-   iii) high-resistance devices (about 30 l/min).

The reported flow rates refer to the pressure drop of 4 KPa (KiloPascal)in accordance to the European Pharmacopoeia (Eur Ph).

Drugs intended for inhalation as dry powders should be used in the formof micronised powder so they are characterised by particles of fewmicrons (μm) particle size. Said size is quantified by measuring acharacteristic equivalent sphere diameter, known as aerodynamicdiameter, which indicates the capability of the particles of beingtransported suspended in an air stream. Hereinafter, we consider asparticle size the mass median aerodynamic diameter (MMAD). Respirableparticles are generally considered to be those with diameters from 0.5to 6 μm, as they are capable of penetrating into the lower lungs, ie thebronchiolar and alveolar sites, where absorption takes place. Largerparticles are mostly deposited in the oropharyngeal cavity so theycannot reach said sites, whereas the smaller ones are exhaled.

Although micronisation of the active drug is essential for depositioninto the lower lungs during inhalation, it is also known that the finerare the particles, the stronger are the cohesion forces. Strong cohesionforces hinder the handling of the powder during the manufacturingprocess (pouring, filling). Moreover they reduce the flowability of theparticles while favouring the agglomeration and/or adhesion thereof tothe walls. In multidose DPI's, said phenomena impair the loading of thepowder from the reservoir to the aerosolization chamber, so giving riseto handling and metering accuracy problems.

Poor flowability is also detrimental to the respirable fraction of thedelivered dose, the active particles being unable to leave the inhalerand remaining adhered to the interior of the inhaler, or leaving theinhaler as large agglomerates; agglomerated particles, in turn, cannotreach the bronchiolar and alveolar sites of the lungs. The uncertaintyas to the extent of agglomeration of the particles between eachactuation of the inhaler and also between inhalers and different batchesof particles, leads to poor dose reproducibility as well.

In the prior art, one possible method of improving the flowingproperties of these powders is to agglomerate, in a controlled manner,the micronised particles to form spheres of relatively high density andcompactness. The process is termed spheronisation while the roundparticles formed are called pellets. When, before spheronisation, theactive ingredient is mixed with a plurality of fine particles of one ormore excipients, the resulting product has been termed as soft pellets.

Otherwise powders for inhalation could be formulated by mixing themicronised drug with a carrier material (generally lactose, preferablyα-lactose monohydrate) consisting of coarser particles to give rise toso-called ‘ordered mixtures’.

However, either ordered mixtures and pellets should be able toeffectively release the drug particles during inhalation, in order toallow them to reach the target site into the lungs.

In this regard, it is well known that the interparticle forces whichoccur between the two ingredients in the ordered mixtures may turn outto be too high thus preventing the separation of the micronised drugparticles from the surface of the coarse carrier ones during inhalation.The surface of the carrier particles is, indeed, not smooth but hasasperities and clefts, which are high energy sites on which the activeparticles are preferably attracted to and adhere more strongly. Inaddition, ordered mixtures consisting of low strength active ingredientscould also face problems of uniformity of distribution and hence ofmetering accurate doses.

On the other hand, soft pellets may reach a so high internal coherenceas to compromise their breaking up into the small particles duringinhalation; such drawback could be regarded as a particular criticalstep when high-resistance dry powder inhalers are used. With saidinhalers, less energy is indeed available for breaking up the pelletsinto the small primary particles of the active ingredient. The softpellets may also face some problems of handling during filling and useof the inhalers.

In consideration of all problems and disadvantages outlined, it would behighly advantageous to provide a formulation aimed at delivering lowstrength active ingredients after inhalation with a DPI device,preferably a high-resistance one and exhibiting: i) good uniformity ofdistribution of the active ingredient; ii) small drug dosage variation(in other words, adequate accuracy of the delivered doses); iii) goodflowability; iv) adequate physical stability in the device before use;v) good performance in terms of emitted dose and fine particle fraction(respirable fraction).

Another requirement for an acceptable formulation is its adequateshelf-life.

It is known that the chemical compounds can undergo chemico-physicalalterations such as amorphisation, when subjected to mechanicalstresses. Amorphous or partially amorphous materials, in turn, absorbwater in larger amounts than crystalline ones (Hancock et al. J. Pharm.Sci. 1997, 86, 1-12) so formulations containing active ingredients,whose chemical stability is particularly sensitive to the humiditycontent, will benefit during their preparation by the use of as low aspossible energy step treatment.

Therefore, it would be highly advantageous to provide a process forpreparing said formulation in which a low energy step is envisionedduring the incorporation of the active ingredient to the mixture in sucha way to ensure adequate shelf life of the formulation suitable forcommercial distribution, storage and use.

OBJECT OF THE INVENTION

It is an object of the invention to provide a formulation to beadministered as dry powder for inhalation suitable for efficaciousdelivery of active ingredients into the low respiratory tract ofpatients suffering from pulmonary diseases such as asthma. Inparticular, it is an object of the invention to provide a formulation tobe administered as dry powder for inhalation which is freely flowable,can be produced in a simple way, physically and chemically stable and iscapable of delivering accurate doses and/or high fine particle fractionof active ingredients.

According to a first embodiment of the invention there is provided apowder for use in a dry powder inhaler comprising: i) a fraction of fineparticle size constituted of a mixture of a physiologically acceptableexcipient and an additive, the mixture having a mean particle size ofless than 35 μm; ii) a fraction of coarse particles constituted of aphysiologically acceptable carrier having a particle size of at least 90μm; and iii) at least one active ingredient, said mixture (i) beingcomposed of up to 99% by weight of particles of the excipient and atleast 1% by weight of additive and the ratio between the fine excipientparticles and the coarse carrier particles being between 1:99 and 40:60%by weight.

In a preferred embodiment of the invention, the fraction (i) is preparedin such a way that the additive particles are attached on the surface ofthe excipient particles. Said feature, in turn, can be achieved eitherby co-micronising the excipient particles and the additive particles orby mixing the excipient particles in the micronised form and theadditive particles in a Turbula or a high energy mixer.

Suitable mixers for carrying out a high energy mixing step in thecontext of such formulatins are high shear mixers. Such mixers are knownto those skilled in the art, and include, for example, the Cyclomix andthe Mechano-Fusion mixers manufactured by Hosokawa Micron. It will beappreciated by those skilled in the art that other suitable apparatus oruse in a high energy mixing step will include, for example, ball millsand jet mills, provided that the equipment and conditions are soarranged to provide the desired high energy mixing.

In one particular embodiment of the invention, the additive materialparticles partially coat the surface of the excipient particles and/orthe coarse carrier particles. That may be achieved in the case ofcertain water-insoluble additives such as in particular magnesiumstearate and other stearic esters, stearic acid, and other fatty acidsand esters by exploiting their peculiar film forming properties as alsoreported in International Specification WO 00/53157. The coating can beestablished by scanning electron microscope and the degree of coatingcan be evaluated by means of image analysis methods.

It is preferable that the additive particles should, at least partially,coat the surface of both the excipient and the coarse carrier particles.

It has been found that the particle size of the physiologicallyacceptable excipient, the main component of the mixture (i) is ofparticular importance and that the best results in terms of aerosolperformances are achieved when its particle size is less than 35 μm,preferably less than 30, more preferably less than 20, even morepreferably less than 15 μm.

In a more preferred embodiment, the formulation of the invention is inthe form of ‘hard pellets’ and they are obtained by subjecting themixture to a spheronisation process.

By the term ‘hard pellets’ we mean spherical or semi-spherical unitswhose core is made of coarse particles. The term has been coined fordistinguishing the formulation of the invention from the soft pellets ofthe prior art which are constituted of only microfine particles (WO95/24889, GB 1520247, WO 98/31353).

By the term ‘spheronisation’ we mean the process of rounding off of theparticles which occurs during the treatment.

In an even more preferred embodiment of the invention, the coarsecarrier particles have a particle size of at least 175 μm as well as ahighly fissured surface. A carrier of the above mentioned particle sizeis particularly advantageous when the fine excipient particlesconstitute at least 10% by weight of the final formulation. It has beenfound that, whereas formulations containing conventional carriers andhaving fine particle contents of above 5% tend to have poor flowproperties, and above 10 tend to have very poor flow properties, theformulations according to that preferred embodiment of the inventionhave adequate flow properties even at fines contents (that is contentsof active particles and of fine excipient particles) of up to 40% byweight.

The prior art discloses several approaches for improving the flowabilityproperties and the respiratory performances of low strength activeingredients. WO 98/31351 claims a dry powder composition comprisingformoterol and a carrier substance, both of which are in finely dividedform wherein the formulation has a poured bulk density of from 0.28 to0.38 g/ml. Said formulation is in the form of soft pellet and does notcontain any additive.

EP 441740 claims a process and apparatus thereof for agglomerating andmetering non-flowable powders preferably constituted of micronisedformoterol fumarate and fine particles of lactose (soft pellets).

Furthermore several methods of the prior art were generally addressed atimproving the flowability of powders for inhalation and/or reducing theadhesion between the drug particles and the carrier particles.

-   GB 1,242,211, GB 1,381,872 and GB 1,571,629 disclose pharmaceutical    powders for the inhalatory use in which the micronised drug (0.01-10    μm) is respectively mixed with carrier particles of sizes 30 to 80    μm, 80 to 150 μm, and less than 400 μm wherein at least 50% by    weight of which is above 30 μm.-   WO 87/05213 describes a carrier, comprising a conglomerate of a    solid water-soluble carrier and a lubricant, preferably 1% magnesium    stearate, for improving the technological properties of the powder    in such a way as to remedy to the reproducibility problems    encountered after the repeated use of a high resistance inhaler    device.-   WO 96/02231 claims a mixture characterised in that the micronised    active compound is mixed with rough carrier particles having a    particle size of 400 μm to 1000 μm. According to a preferred    embodiment of the invention, the components are mixed until the    carrier crystals are coated with the fine particles (maximum for 45    minutes). No example either with auxiliary additives and/or with low    strength active ingredient is reported.-   EP 0,663,815 claims the addition of finer particles (<10 μm) to    coarser carrier particles (>20 μm) for controlling and optimising    the amount of delivered drug during the aerosolisation phase.-   WO 95/11666 describes a process for modifying the surface properties    of the carrier particles by dislodging any asperities in the form of    small grains without substantially changing the size of the    particles. Said preliminary handling of the carrier causes the    micronised drug particles to be subjected to weaker interparticle    adhesion forces.-   In WO 96/23485, carrier particles are mixed with an anti-adherent or    anti-friction material consisting of one or more compounds selected    from amino acids (preferably leucine); phospholipids or surfactants;    the amount of additive and the process of mixing are preferably    chosen in such a way as to not give rise to a real coating. The    inventor believes that the presence of a discontinuous covering as    opposed to a “coating” is an important and advantageous feature. The    carrier particles blended with the additive are preferably subjected    to the process disclosed in WO 95/11666.-   Kassem (London University Thesis 1990) disclosed the use of    relatively high amount of magnesium stearate (1.5%) for increasing    the ‘respirable’ fraction. However, the reported amount is too great    and reduces the mechanical stability of the mixture before use.-   WO 00/28979, which was published after the earliest priority date of    this application, describes the use of small amounts of magnesium    stearate for improving stability to humidity of dry powder    formulations for inhalation.-   WO 00/33789, also published after the earliest priority date of this    application, describes an excipient powder for inhalable drugs    comprising a coarse first fraction, a fine second fraction, and a    ternary agent which may be leucine.

In none of aforementioned documents the features of the formulation ofthe invention are disclosed and none of the teaching therein disclosedcontributes to the solution of the problem according to the invention.All the attempts of obtaining stable powder formulations of low strengthactive ingredients endowed of good flowability and high fine particlefraction according to some of the teaching of the prior art, for exampleby preparation of ordered mixture, addition of a fine fraction, mereaddition of additives, were indeed unsuccessful as demonstrated by theexamples reported below. In particular, in the prior art it oftenoccurred that the solutions proposed for a technical problem (ieimproving dispersion of the drug particles) was detrimental to thesolution of another one (ie improving flowability, mechanical stability)or vice versa. On the contrary, the formulation of the invention showseither excellent Theological properties and physical stability and goodperformances in terms of fine particle fraction, preferably more than40%. The cohesiveness between the partners has been indeed adjusted insuch a way as to give sufficient adhesion force to hold the activeparticles to the surface of the carrier particles during manufacturingof the dry powder and in the delivery device before use, but to allowthe effective dispersion of the active particles in the respiratorytract even in the presence of a poor turbulence as that created byhigh-resistance devices.

Contrary to what has been stated in the prior art (EP 441740), in theformulation of the invention the presence of an additive does notnecessarily compromise the integrity of the pellets before use.

According to a second embodiment of the invention there are alsoprovided a process for making the formulation of the invention, in sucha way that the additive particles partially coat the surface of eitherthe excipient particles and the coarse carrier particles.

According to a particular embodiment, there is provided a processincluding the steps of: i) co-micronising the excipient particles andthe additive particles so as to reduce their particle size below 35 μm,and contemporaneously making the additive particles partially coat thesurface of the excipient particles; ii) spheronising by mixing theresulting mixture with the coarse carrier particles such that mixtureparticles adhere to the surface of the coarse carrier particles; iii)adding by mixing the active particles to the spheronised particles.

According to a further particular embodiment of the invention there isprovided another process, said process including the steps of: i) mixingthe excipient particles in the micronised form and the additiveparticles in such a way as to make the additive particles partially coatthe surface of the excipient particles; ii) spheronising by mixing theresulting mixture with the coarse carrier particles such that mixtureparticles adhere to the surface of the coarse carrier particles; iii)adding by mixing the active particles to the spheronised particles.

When the coarse carrier particles have a particle size of at least 175μm and in a preferred embodiment a highly fissured surface, theformulation of the invention could also be prepared by: i) co-mixing thecoarse carrier particles, magnesium stearate and the fine excipient.particles; ii) adding by mixing the active particles to the mixture.

It has been indeed found advantageous in some cases for the particles tobe processed for at least two hours, to have a good fine particlefraction (respirable fraction) and no problem of sticking during thepreparation.

Contrary to the prior art (WO 98/31351), the active ingredient may beincorporated in the mixture by simple mixing so avoiding any potentialmechanical stress which may disturb the crystallinity of its particles.

Advantageously, the coarse and fine carrier particles may be constitutedof any pharmacologically acceptable inert material or combinationthereof; preferred carriers are those made of crystalline sugars, inparticular lactose; the most preferred are those made of α-lactosemonohydrate. Advantageously the diameter of the coarse carrier particlesis at least 100 μm, more advantageously at least 145 μm, preferably atleast 175 μm, more preferably between 175 and 400 μm, even morepreferably between 210 and 355 μm.

A number of methods may be used to determine whether carrier particleshave such a fissured surface, which will offer the capability ofretaining relatively large fines contents substantially withoutsegregation:

1. Determination of tapped density.

The tapped density of the fissured carrier particles may be about 6% ormore, and preferably 15% or more, lower than the tapped density ofcarrier particles of the same material and of particle characteristicsof a kind typical of carrier particles which have conventionally beenused in the manufacture of inhalable powders. In the case of fissuredcarrier particles of crystalline sugars, for example lactose, the tappeddensity of the fissured particles is not more than 0.75 g/cm³, andpreferably not more than 0.70 g/cm³. The tapped density of lactosegrades conventionally used in the manufacture of commercial DPIformulations is typically about 0.8 g/cm³. Tapped densities referred toherein may be measured as follows:

A measuring cylinder is weighed on a top pan balance (2 place).Approximately 50 g powder is introduced into the measuring cylinder, andthe weight is recorded. The measuring cylinder containing the powder isattached to a jolting volumeter (Jel Stampfvolumeter). The joltingvolumeter is set to tap 200 times. During each tap, the measuringcylinder is raised and allowed to fall a set distance. After the 200taps, the volume of the powder is measured. The tapping is repeated andthe new volume measured. The tapping is continued until the powder willsettle no more. The tapped density is calculated as the weight of thepowder divided by the final tap volume. The procedure is performed threetimes (with new powder each time) for each powder measured, and the meantapped density calculated from those three final tapped volume values.

2. Mercury Intrusion Porosimetry. Mercury intrusion porosimetry assessesthe pore size distribution and the nature of the surface and porestructure of the particles. Porosimetry data is suitably collected overpressure range 3.2 kPa to 8.7 MPa, for example, using an Autopore 9200II Porosimeter (Micromeritics, Norcross, USA). Samples should beevacuated to below 5 Pa prior to analysis to remove air and looselybound surface water. Suitable lactose is characterised by a bulk densityof not more than 0.65 g/cm³ and preferably not more than 0.6 g/cm³.Suitable lactose is also characterised by a total intrusion volume, asmeasured by mercury intrusion porosimetry, of at least 0.8 cm³ g⁻¹ andpreferably at least 0.9 cm³g⁻¹. (It has been found that lactose having abulk density of 0.6 g/cm³ as measured by mercury intrusion porosimetryhas a tapped density of about 0.7 g/cm³, whereas the discrepancy betweenthe two methods at lower densities is less.)3. “Fissure Index”. The term “fissure index” used herein refers to theratio of a theoretical envelope volume of the particles, as calculatedfrom the envelope of the particles, to the actual volume of theparticles, that is, omitting fissures within the envelope. Suitableparticles are those having a fissure index of at least 1.25. Thetheoretical envelope volume may be determined optically, for example, byexamining a small sample of the particles using an electron microscope.The theoretical envelope volume of the particles may be estimated viathe following method. An electron micrograph of the sample may bedivided into a number of grid squares of approximately equalpopulations, each containing a representative sample of the particles.The population of one or more grids may then be examined and theenvelope encompassing each of the particles determined visually asfollows. The Feret's diameter for particles within a grid is measuredrelative to a fixed axis of the image. Typically at least ten particlesare measured for their Feret's diameter. Feret's diameter is defined asthe length of the projection of a particle along a given reference lineas the distance between the extreme left and right tangents that areperpendicular to the reference line. A mean Feret's diameter is derived.A theoretical mean envelope volume may then be calculated from this meandiameter to give a representative value for all the grid squares andthus the whole sample. Division of that value by the number of particlesgives the mean value per particle. The actual volume of the particlesmay then be calculated as follows. First, the mean mass of a particle iscalculated. A sample of approximately 50 mg is taken and its preciseweight recorded to 0.1 mg. Then by optical microscopy the precise numberof particles in that sample is determined. The mean mass of one particlecan then be determined. The procedure is then repeated five times toobtain a mean value of this mean. Second, a fixed mass of particles(typically 50 g), is weighed out accurately, and the number of particleswithin this mass is calculated using the above mean mass value of oneparticle. Finally, the sample of particles is immersed in a liquid inwhich the particles are insoluble and, after agitation to remove trappedair, the amount of liquid displaced is measured. From this the meanactual volume of one particle can be calculated. The fissure index isadvantageously not less than 1.5, and is, for example, 2 or more.4. “Rugosity Coefficient”. The rugosity coefficient is used to mean theratio of the perimeter of a particle outline to the perimeter of the‘convex hull’. This measure has been used to express the lack ofsmoothness in the particle outline. The ‘convex hull’ is defined as aminimum enveloping boundary fitted to a particle outline that is nowhereconcave. (See “The Shape of Powder-Particle Outlines” A. E. Hawkins,Wiley.) The ‘rugosity coefficient’ may be calculated optically asfollows. A sample of particles should be identified from an electronmicrograph as identified above. For each particle the perimeter of theparticle outline and the associated perimeter of the ‘convex hull’ ismeasured to provide the rugosity coefficient. This should be repeatedfor at least ten particles to obtain a mean value. The mean rugositycoefficient is at least 1.25.

Carrier particles which have the above-mentioned capability of retainingrelatively large amounts of fine material without or with only littlesegregation will generally comply with all of Methods 1 to 4 above, butfor the avoidance of doubt any carrier particles which comply with atleast one of Methods 1 to 4 is deemed to be a fissured particle.

The additive material, which is preferably on the surfaces of thecarrier particles, promotes the release of the active particles from thecarrier particles on actuation of the inhaler device. The formulationcontaining the additive material should, however, be such that theactive particles are not liable to be released form the carrierparticles before actuation of the inhaler device. The additive material,which it will be appreciated is of a different material from the carrierparticles, may be in the form of particles, the additive particles beingattached to the surfaces of the carrier particles.

In International Specification WO 96/23485 many examples are given ofadditive materials which are such that the active particles are notliable to be released from the carrier particles before actuation of theinhaler device but are released during use of the inhaler device.“Actuation of the inhaler device” refers to the process during which adose of the powder is removed from its rest position in the inhalerdevice, usually by a patient inhaling. That step takes place after thepowder has been loaded into the inhaler device ready for use.

If it is desired to test whether or not the active particles of a powderare liable to be released from the carrier particles before actuation ofthe inhaler device a test can be carried out. A suitable test isdescribed in International Specification WO96/23485 (Examples 12 and13). A powder whose post-vibration homogeneity measured as a percentagecoefficient of variation, after being subjected to the described test,is less than about 5% can be regarded as acceptable.

It is believed that additive material is attracted to and adheres tohigh energy sites on the surfaces of the carrier particles. Onintroduction of the active particles, many of the high energy sites arenow occupied, and the active particles therefore occupy the lower energysites on the surfaces of the carrier particles. That results in theeasier and more efficient release of the active particles in the airstream created on inhalation, thereby giving increased deposition of theactive particles in the lungs.

However, as indicated above, it has been found that the addition of morethan a small amount of additive material can be disadvantageous becauseof the adverse effect on the ability to process the mix duringcommercial manufacture.

It is also advantageous for as little as possible of the additivematerial to reach the lungs on inhalation of the powder. Although theadditive material will most advantageously be one that is safe to inhaleinto the lungs, it is still preferred that only a very small proportion,if any, of the additive material reaches the lung, in particular thelower lung. The considerations that apply when selecting the additivematerial and other features of the powder are therefore different fromthe considerations when a third component is added to carrier and activematerial for certain other reasons, for example to improve absorption ofthe active material in the lung, in which case it would of course beadvantageous for as much as possible of the additive material in thepowder to reach the lung.

The optimum amount of additive material will depend on the chemicalcomposition and other properties of the additive material. In general,the amount of additive will be not more than 50% by weight, based on thetotal weight of the formulations. However, it is thought that for mostadditives the amount of additive material should be not more than 10%,more advantageously not more than 5%, preferably not more than 4% andfor most materials will be not more than 2% or even not more than 1% byweight or not more than 0.25% based on the total weight of theformulation. In general, the amount of additive material is at least0.01% by weight based on the total weight of the formulation.

Advantageously the additive material is an anti-adherent material andwill tend to decrease the cohesion between the anti-adherent materialsand the carrier particles. In order to determine whether a givenmaterial is an anti-adherent material, the test described inInternational Specification WO97/03649 (pages 6 and 7) using an“Aeroflow” apparatus may be used, anti-adherent materials being thoseadditive materials that result in a lowering of the mean time betweenavalanches of the powder, as compared with the powder in the absence ofthe additive material.

Advantageously the additive material is an anti-friction agent (glidant)and will give better flow of powder in the dry powder inhaler which willlead to a better dose reproducibility from the inhaler device.

Where reference is made to an anti-adherent material, or to ananti-friction agent, the reference is to include those materials whichwill tend to decrease the cohesion between the active particles and thecarrier particles, or which will tend to improve the flow of powder inthe inhaler, even though they may not usually be referred to asanti-adherent material or an anti-friction agent. For example, leucineis an anti-adherent material as herein defined and is generally thoughtof as an anti-adherent material but lecithin is also an anti-adherentmaterial as herein defined, even though it is not generally though of asbeing anti-adherent, because it will tend to decrease the cohesionbetween the active particles and the carrier particles. Advantageously,the additive material consists of physiologically acceptable material.As already indicated, it is preferable for only small amounts ofadditive material to reach the lower lung, and it is also highlypreferable for the additive material to be a material which may besafely inhaled into the lower lung where it may be absorbed into theblood stream. That is especially important where the additive materialis in the form of particles.

The additive material may include a combination of one or morematerials.

It will be appreciated that the chemical composition of the additivematerial is of particular importance.

It will furthermore be appreciated that additive materials that arenaturally occurring animal or plant substances will offer certainadvantages.

Advantageously, the additive material includes one or more compoundsselected from amino acids and derivatives thereof, and peptides andpolypeptides having molecular weight from 0.25 to 100 Kda, andderivatives thereof. Amino acids, peptides or polypeptides and theirderivatives are both physiologically acceptable and give acceptablerelease of the active particles on inhalation.

It is particularly advantageous for the additive material to comprise anamino acid. Amino acids have been found to give, when present in lowamounts in a powder as additive material, high respirable fraction ofthe active materials with little segregation of the powder and also withvery little of the amino acid being transported into the lower lung. Inrespect of leucine, a preferred amino acid, it is found that, forexample, for an average dose of powder only about 10 μg of leucine wouldreach the lower lung. The additive material may comprise one or more ofany of the following amino acids: leucine, isoleucine, lysine, valine,methionine, phenylalanine. The additive may be a salt of a derivative ofan amino acid, for example aspartame or acesulfame K. Preferably, theadditive particles consist substantially of leucine, advantageouslyL-leucine. As indicated above, leucine has been found to giveparticularly efficient release of the active particles on inhalation.Whilst the L-form of an amino acid is used in Examples described below,the D- and DL-forms may also be used.

Additive materials which comprise one or more water soluble substancesoffer certain advantages. This helps absorption of the substance by thebody if the additive reaches the lower lung. The additive material mayinclude dipolar ions, which may consist of zwitterions.

Alternatively, the additive material may comprise particles of aphospholipid or a derivative thereof. Lecithin has been found to be agood material for the additive material.

The additive material may include or consist of one or more surfaceactive materials, in particular materials that are surface active in thesolid state, which may be water soluble, for example lecithin, inparticular soya lecithin, or substantially water insoluble, for examplesolid state fatty acids such as lauric acid, palmitic acid, stearicacid, erucic acid, behenic acid, or derivatives (such as esters andsalts) thereof. Specific examples of such materials are: magnesiumstearate; sodium stearyl fumarate; sodium stearyl lactylate;phospatidylcholines, phosphatidylglycerols and other examples of naturaland synthetic lung surfactants; liposomal formulations; lauric acid andits salts, for example, sodium lauryl sulphate, magnesium laurylsulphate; triglycerides such as Dynsan 118 and Cutina HR; and sugaresters in general.

Other possible additive materials include talc, titanium dioxide,aluminium dioxide, silicon dioxide and starch.

The expression “additive material” as used herein does not includecrystalline sugars. Whereas small particles of one or more crystallinesugars may be present, and are indeed preferred to be present, asdescribed below, formulations which contain small crystalline sugarparticles will also contain a further substance which is an additivematerial in the sense in which that expression is used herein.

In the case of certain additive materials, it is important for theadditive material to be added in a small amount. For example, magnesiumstearate is highly surface active and should therefore be added in smallamounts, for example, 2% by weight based on the weight of theformulation; phosphatidylcholines and phosphatidylgycerols on the otherhand are less active and can usefully be added in greater amounts; inrespect of leucine, which is still less active, an addition of 2% byweight leucine based on the weight of the powder gives good results inrespect of the respirable fraction of the active particles, lowsegregation and low amount of leucine reaching the lower lung; it isexplained in WO 96/23485 that an addition of a greater amount does notimprove the results and in particular does not significantly improve therespirable fraction and therefore whilst even with 6% leucine areasonable result is obtained that is not preferred since it results inan increased quantity of additive material being taken into the body andwill adversely affect the processing properties of the mix. In thepreferred formulations of the present invention using fissured carrierparticles, however, it has been found that increased amounts of additivematerial may be used and give improved respirable fractions.

The additive material will often be added in particulate form but it maybe added in liquid or solid form and for some materials, especiallywhere it may not be easy to form particles of the material and/or wherethose particles should be especially small, it may be preferred to addthe material in a liquid, for example as a suspension or a solution.Even then, however, the additive material of the finished powder may bein particulate form. An alternative possibility, however, that is withinthe scope of the invention is to use an additive material which remainsliquid even in the final essentially particulate material which canstill be described as a “dry powder”.

In some cases improved clinical benefits will be obtained where theadditive material is not in the form of particles of material. Inparticular, the additive material is less likely to leave the surface ofthe carrier particle and be transported into the lower lung.

Where the additive material of the finished powder is particulate, thenature of the particles may be significant. The additive particles maybe non-spherical in shape. Advantageously, the additive particles areplate-like particles. Alternatively, the additive particles may beangular for example prisms, or dendritic in shape. Additive particleswhich are non-spherical may be easier to remove from the surfaces of thecarrier particles than spherical, non-angular particles and plate-likeparticles may give improved surface interaction and glidant actionbetween the carrier particles.

The surface area of the additive particles is also thought to beimportant. The surface area of the additive particles, as measured usinggas absorption techniques, is preferably at least 5 m²g⁻¹. In many casesit is found that additive material comprising small plate-like particlesis preferred.

The additive may advantageously be magnesium stearate. Advantageously,the amount of magnesium stearate in the final formulation is comprisedbetween at least 0.02 and not more than 2.5% by weight (which equates to2.5 g per 100 g of final formulation). The amount of magnesium stearatemay be between at least 0.05 and not more than 1.0% by weight, forexample between 0.1 and not more than 0.6% by weight, or between 0.2 and0.4% by weight. In some circumstances, in particular where the preferredfissured carrier particles are used, the amount of magnesium stearatemay be preferred to be between 0.1 and 2% by weight, for example 0.5 to1.7% by weight, especially 0.75 to 1.5% by weight. Advantageously thefraction with a fine particle size is composed of 90 to 99% by weight ofthe physiologically acceptable excipient and 1 to 10% by weight of theadditive and the ratio between the fraction of fine particle size andthe fraction of coarse carrier particle is comprised between 1:99 and40:60% by weight, preferably between 5:95 and 30:70 percent by weight,even more preferably between 10:90 and 20:80% by weight.

The fine excipient particles of the mixture (i) in general constituteless than 40% by weight of the total formulation, and advantageouslyconstitute no more than 20%, for example no more than 10%, of the totalformulation weight. Preferably, the fine excipient particles constituteat least 4%, more preferably at least 5% of the total formulationweight.

In a preferred embodiment of the invention, the fraction with a fineparticle size is composed of 98% by weight of α-lactose monohydrate and2% by weight of magnesium stearate and the ratio between the fractionwith a fine particle size and the coarse fraction made of α-lactosemonohydrate particles is 10:90% by weight, respectively.

Advantageously the formulation of the invention has an apparent densitybefore settling of at least 0.5 g/ml, preferably from 0.6 to 0.7 g/mland a Carr index of less than 25, preferably less than 15.

In one of the embodiment of the invention, the excipient particles andadditive particles are co-micronised by milling, advantageously in aball mill, preferably until the final particle size of the mixture isless than 35 μm, preferably less than 30 μm, more preferably less than15 μm. In some cases, co-micronisation for at least two hours may befound advantageous, although it will be appreciated that the time oftreatment will generally be such that a desired size reduction isobtained. In a more preferred embodiment of the invention the particlesare co-micronised by using a jet mill.

Alternatively, the mixture of the excipient particles with a startingparticle size less than 35 μm, preferably less than 30 μm, morepreferably less than 15 μm, with the additive particles will be preparedby mixing the components in a high-energy mixer for at least 30 minutes,preferably for at least one hour, more preferably for at least twohours.

In general, the person skilled in the art will select the most propersize of the fine excipient particles either by sieving, by using aclassifier, or by suitably adjusting the time of co-milling.

The spheronisation step will be carried out by mixing the coarse carrierparticles and the fine particle fraction in a suitable mixer, e.g.tumbler mixers such as Turbula, rotary mixers or instant mixer such asDiosna for at least 5 minutes, preferably for at least 30 minutes, morepreferably for at least two hours, even more preferably for four hours.In a general way, the person skilled in the art will adjust the time ofmixing and the speed of rotation of the mixer to obtain homogenousmixture.

When the formulation of the invention is prepared by co-mixing thecoarse carrier particles, additive and the fine excipient particles alltogether, the process is advantageously carried out in a suitable mixer,preferably in a Turbula mixer for at least two hours, preferably for atleast four hours.

The ratio between the spheronised carrier and the drug (the activeingredient) will depend on the type of inhaler device used and therequired dose.

The mixture of the spheronised carrier with the active particles will beprepared by mixing the components in suitable mixers like those reportedabove.

Advantageously, at least 90% of the particles of the drug have aparticle size less than 10 μm, preferably less than 6 μm.

The at least one active ingredient is preferably in the form of activeparticles. The active particles referred to throughout the specificationwill comprise an effective amount of at least one active agent that hastherapeutic activity when delivered into the lung. The active particlesadvantageously consist essentially of one or more therapeutically activeagents. Suitable therapeutically active agents may be drugs fortherapeutic and/or prophylactic use. Active agents which may be includedin the formulation include those products which are usually administeredorally by inhalation for the treatment of disease such a respiratorydisease, for example, β-agonists.

The active particles may comprise at least one β-agonist, for exampleone or more compounds selected from terbutaline, salbutamol, salmeteroland formoterol. If desired, the active particles may comprise more thanone of those active agents, provided that they are compatible with oneanother under conditions of storage and use. Preferably, the activeparticles are particles of salbutamol sulphate. References herein to anyactive agent are to be understood to include any physiologicallyacceptable derivative. In the case of the β-agonists mentioned above,physiologically acceptable derivatives include especially salts,including sulphates.

The active particles may be particles of ipatropium bromide.

The active particles may include a steroid, which may be, for example,fluticasone. The active principle may include a cromone which may besodium cromoglycate or nedocromil. The active principle may include aleukotriene receptor antagonist.

The active particles may include a carbohydrate, for example heparin.

The active particles may advantageously comprise a therapeuticallyactive agent for systemic use provided that that agent is capable ofbeing absorbed into the circulatory system via the lungs. For example,the active particles may comprise peptides or polypeptides or proteinssuch as DNase, leukotrienes or insulin (including substituted insulinsand pro-insulins), cyclosporin, interleukins, cytokines, anti-cytokinesand cytokine receptors, vaccines (including influenza, measles,‘anti-narcotic’ antibodies, meningitis), growth hormone, leuprolide andrelated analogues, interferons, desmopressin, immunoglobulins,erythropoeitin, calcitonin and parathyroid hormone. The formulation ofthe invention may in particular have application in the administrationof insulin to diabetic patients, thus avoiding the normally invasiveadministration techniques used for that agent.

The powders of the invention may advantageously be for use in painrelief. Non-opioid analgesic agents that may be included as pain reliefagents are, for example, alprazolam, amitriptyline, aspirin, baclofen,benzodiazepines, bisphosphonates, caffeine, calcitonin,calcium-regulating agents, carbamazepine, clonidine, corticosteroids,dantrolene, dexamethasone, disodium pamidronate, ergotamine, flecainide,hydroxyzine, hyoscine, ibuprofen, ketamine, lignocaine, lorazepam,methotrimeprazine, methylprednisolone, mexiletine, mianserin, midazolam,NSAIDs, nimodipine, octreotide, paracetamol, phenothiazines,prednisolone, somatostatin. Suitable opioid analgesic agents are:alfentanil hydrochloride, alphaprodine hydrochloride, anileridine,bezitramide, buprenorphine hydrochloride, butorphanol tartrate,carfentanil citrate, ciramadol, codeine, dextromoramide,dextropropoxyphene, dezocine, diamorphine hydrochloride, dihydrocodeine,dipipanone hydrochloride, enadoline, eptazocine hydrobromide,ethoheptazine citrate, ethylmorphine hydrochloride, etorphinehydrochloride, fentanyl citrate, hydrocodone, hydromorphonehydrochloride, ketobemidone, levomethadone hydrochloride, levomethadylacetate, levorphanol tartrate, meptazinol hydrochloride, methadonehydrochloride, morphine, nalbuphine hydrochloride, nicomorphinehydrochloride, opium, hydrochlorides of mixed opium alkaloids,papaveretum, oxycodone, oxymorphone hydrochloride, pentamorphone,pentazocine, pethidine hydrochloride, phenazocine hydrobromide,phenoperidine hydrochloride, picenadol hydrochloride, piritramide,propiram furmarate, remifentanil hydrochloride, spiradoline mesylate,sufentanil citrate, tilidate hydrochloride, tonazocine mesylate,tramadol hydrochloride, trefentanil.

The technique could also be used for the local administration of otheragents for example for anti cancer activity, anti-virals, antibiotics,muscle relaxants, antidepressants, antiepileptics or the local deliveryof vaccines to the respiratory tract.

In one form of the invention, the active ingredient is not an activeingredient selected from the group consisting of budesonide and itsepimers, formoterol, TA2005 and its steroisomers, salts thereof andcombinations thereof.

The active particles advantageously have a mass median aerodynamicdiameter in the range of up to 15 μm, for example from 0.01 to 15 μm,preferably from 0.1 to 10 μm, for example from 1 to 8 μm. Mostpreferably, the mass median aerodynamic diameter of the active particlesis not exceeding 5 μm. The active particles are present in an effectiveamount, for example, at least 0.01% by weight, and may be present in anamount of up to 90% by weight based on the total weight of carrierparticles, additive materials and active particles. Advantageously, theactive particles are present in an amount not exceeding 60% by weightbased on the total weight of carrier particles, additive particles andactive particles.

It will be appreciated that the proportion of active agent present willbe chosen according to the nature of the active agent. In many cases, itwill be preferred for the active agent to constitute no more than 10%,more preferably no more than 5%, and especially no more than 2% byweight based on the total weight of carrier particles, additiveparticles and active particles.

The process of the invention is illustrated by the following examples.

EXAMPLE 1 Hard-pellet Formulation Containing Coarse Lactose (CapsuLac212-355 μm) a Micronized Pre-blend Lactose/Magnesium Stearate MixtureObtained by Jet Milling and Formoterol Fumarate as Active Ingredient

a) Preparation of the Formulation

α-Lactose monohydrate SpheroLac 100 (Meggle EP D30) with a startingparticle size of 50 to 400 μm (d(v, 0.5) of about 170 μm) and magnesiumstearate with a starting particle size of 3 to 35 μm (d(v, 0.5) of about10 μm) in the ratio 98:2% by weight were co-milled in a jet millapparatus. At the end of the treatment, a significant reduction of theparticle size was observed (blend A).

85% by weight of α-lactose monohydrate CapsuLac (212-355 μm) was placedin a 240 ml stainless steel container, then 15% by weight of blend A wasadded. The blend was mixed in a Turbula mixer for 2 hours at 42 rpm(blend B).

Micronised formoterol fumarate was added to the blend B and mixed in aTurbula mixer for 10 mins at 42 rpm to obtain a ratio of 12 μg of activeto 20 mg of carrier; the amount of magnesium stearate in the finalformulation is 0.3% by weight. The final formulation (hard pelletformulation) was left to stand for 10 mins then transferred to amberglass jar.

b) Characterisation of the Micronised Mixture (Blend A)

The micronized mixture (blend A) was characterised by particle sizeanalysis (Malvern analysis), water contact angle and degree of molecularsurface coating calculated according to Cassie et al. in Transaction ofthe Faraday Society 40; 546,1944.

The results obtained are reported in Table 1.

TABLE 1 Micronised mixture (blend A) Particle size distribution (μm)Malvern d (v, 0.1) 1.58 d (v, 0.5) 4.19 d (v, 0.9) 9.64 Water contactangle 40° Degree of coating 15%* *α-Lactose monohydrate water contactangle 12°; magnesium stearate water contact angle 118°.c) Chemical and Technological Characterisation of the Hard-pelletFormulation.

The formulation mixture was characterised by its density/flowabilityparameters and uniformity of distribution of the active ingredient.

The apparent volume and apparent density were tested according to themethod described in the European Pharmacopoeia (Eur. Ph.).

Powder mixtures (100 g) were poured into a glass graduated cylinder andthe unsettled apparent volume V₀ is read; the apparent density beforesettling (dv) was calculated dividing the weight of the sample by thevolume V₀. After 1250 taps with the described apparatus, the apparentvolume after settling (V₁₂₅₀) is read and the apparent density aftersettling (ds) was calculated.

The flowability properties were tested according to the method describedin the Eur. Ph.

Powder mixtures (about 110 g) were poured into a dry funnel equippedwith an orifice of suitable diameter that is blocked by suitable mean.The bottom opening of the funnel is unblocked and the time needed forthe entire sample to flow out of the funnel recorded. The flowability isexpressed in seconds and tenths of seconds related to 100 g of sample.

The flowability was also evaluated from the Carr's index calculatedaccording to the following formula:

${{{Carr}^{\prime}s\mspace{14mu}{index}\mspace{14mu}(\%)} = {\frac{{\mathbb{d}s} - {\mathbb{d}v}}{\mathbb{d}s} \times 100}}\;$

A Carr index of less than 25 is usually considered indicative of goodflowability characteristics.

The uniformity of distribution of the active ingredient was evaluated bywithdrawing 10 samples, each equivalent to about a single dose, fromdifferent parts of the blend. The amount of active ingredient of eachsample was determined by High-Performance Liquid Chromatography (HPLC).

The results are reported in Table 2.

TABLE 2 Chemical and Technological Parameters of the hard pelletformulation Apparent volume/density App. volume (V₀) before settling 156 ml App. density (d_(v)) before settling 0.64 g/ml App. volume(V₁₂₅₀) after settling  138 ml App. density (d_(s)) after settling 0.73g/ml Flowability Flow rate through 4 mm Ø  152 s/100 g Carr Index 12Uniformity of distribution of active ingredient Mean value 12.1 μg RSD2.2%d) Determination of the Aerosol Performances.

An amount of powder for inhalation was loaded in a multidose dry powderinhaler (Pulvinal®—Chiesi Pharmaceutical SpA, Italy).

The evaluation of the aerosol performances was performed by using amodified Twin Stage Impinger apparatus, TSI (Apparatus of type A for theaerodynamic evaluation of fine particles described in FU IX, 4°supplement 1996). The equipment consists of two different glasselements, mutually connected to form two chambers capable of separatingthe powder for inhalation depending on its aerodynamic size; thechambers are referred to as higher (stage 1) and lower (stage 2)separation chambers, respectively. A rubber adaptor secures theconnection with the inhaler containing the powder. The apparatus isconnected to a vacuum pump which produces an air flow through theseparation chambers and the connected inhaler. Upon actuation of thepump, the air flow carries the particles of the powder mixture, causingthem to deposit in the two chambers depending on their aerodynamicdiameter. The apparatus used were modified in the Stage 1 Jet in orderto obtained an aerodynamic diameter limit value, dae, of 5 μm at an airflow of 30 l/min, that is considered the relevant flow rate forPulvinal® device. Particles with higher dae deposit in Stage 1 andparticles with lower dae in Stage 2. In both stages, a minimum volume ofsolvent is used (30 ml in Stage 2 and 7 ml in Stage 1) to preventparticles from adhering to the walls of the apparatus and to promote therecovery thereof.

The determination of the aerosol performances of the mixture obtainedaccording to the preparation process a) was carried out with the TSIapplying an air flow rate of 30 l/min for 8 seconds.

After nebulization of 10 doses, the Twin Stage Impinger was disassembledand the amounts of drug deposited in the two separation chambers wererecovered by washing with a solvent mixture, then diluted to a volume of100 and 50 ml in two volumetric flasks, one for Stage 1 and one forStage 2, respectively. The amounts of active ingredient collected in thetwo volumetric flasks were then determined by High-Performance LiquidChromatography (HPLC). The following parameters, were calculated: i) theshot weight as mean expressed as mean and relative standard deviation(RSD) ii) the fine particle dose (FPD) which is the amount of drug foundin stage 2 of TSI; iii) the emitted dose which is the amount of drugdelivered from the device recovered in stage 1+stage 2; iv) the fineparticle fraction (FPF) which is the percentage of the emitted dosereaching the stage 2 of TSI.

The results in terms of aerosol performances are reported in Table 3.

TABLE 3 Aerosol performances Shot weight mg (%) Emitted dose μg FPD μgFPF % 20.0 (7.8) 9.40 4.44 47.2

The formulation of the invention shows very good flow properties asdemonstrated by the Carr index; this parameter is very important toobtain consistency of the delivered dose when a multi-dose dry powderinhalers with powder reservoir is used. The aerosol performance of theformulation is very good as well with about 50% of the drug reaching thestage 2 of the TSI.

EXAMPLE 2 Hard-pellet Formulation Containing Coarse Lactose (CapsuLac212-355 μm), a Micronized Pre-blend Lactose/Magnesium Stearate MixtureObtained by Ball Milling and Formoterol Fumarate as Active Ingredient

Blend A was prepared as described in the Example 1 but using α-lactosemonohydrate SorboLac 400 with a starting particle size below 30 μm (d(v,0.5) of about 10 μm) and carrying out the co-micronisation in a ballmilling apparatus for 2 hours.

Blend B was prepared according to the Example 1 but after mixing for 6mins and then screening through a 355 μm sieve.

The hard pellet final formulation was prepared according to the Example1.

The particle size distribution, the water contact angle and the degreeof coating for the micronized mixture (blend A), and the uniformity ofdistribution of the active ingredient for the final formulation (blendB), determined as previously described, are reported in Table 4.Analogous results were achieved after preparing blend B by mixing for 4hours without screening through a sieve.

TABLE 4 Characterisation of blends A and B Micronised mixture (blend A)Particle size distribution (μm) Malvern d (v, 0.1)  0.72 μm d (v, 0.5) 2.69 μm d (v, 0.9) 21.98 μm water contact angle 52° degree of coating25% Final formulation (blend B) Uniformity of distribution of the activeean = 11.84 μg ingredient SD = 1.83%The in-vitro performances, determined as previously described, arereported in Table 5.

TABLE 5 Aerosol performances Shot weight mg (%) Emitted dose μg FPD μgFPF % 20.8 (6.9) 8.57 4.28 49.9As it can be appreciated from the results, also such formulation showexcellent characteristics either in terms of flowability properties andin terms of aerosol performances.

EXAMPLE 3 Determination of the Suitable Amount of Magnesium Stearate tobe Added in the Formulation

Samples of pre-blends were prepared as described in Example 2 in a ballmilling apparatus for 2 hours using α-Lactose monohydrate SorboLac 400(Meggle microtose) with a starting particle size below 30 μm (d(v, 0.5)of about 10 μm) and magnesium stearate with a starting particle size of3 to 35 μm (d(v, 0.5) of about 10 μm) in the ratio 98:2, 95:5 and 90:10%by weight (blends A). Blends B and the hard pellet final formulationwere prepared as previously described; the amount of magnesium stearatein the final formulations turns out to be 0.3, 0.75 and 1.5% by weight,respectively. The uniformity of distribution of active ingredient andthe in-vitro aerosol performance were determined as previouslydescribed.

The results obtained are reported in Table 6.

TABLE 6 Uniformity of distribution and in-vitro aerosol performances Mgstearate Mg stearate Mg stearate 0.3% 0.75% 1.5% Content uniformity Mean(μg) 11.84 — — RSD (%) 1.83 — — Shot weight Mean (mg) 20.8 24.7 23.04.28 49.9 RSD (%) 6.9 6.5 2.4 Emitted dose (μg) 8.57 10.1 11.1 FPD (μg)4.28 3.5 3.6 FPF (%) 49.9 35 32

In all cases, good performances in terms of fine particle dose areobtained, in particular with 0.3% by weight of magnesium stearate in thefinal formulation.

EXAMPLES 4 Ordered Mixtures Powder Formulations

Powders mixtures were prepared by mixing of commercially availablea-lactose monohydrate with different particle size and formoterolfumarate to obtain a ratio of 12 μg of active to 20 mg of carrier.Blending was carried out in glass mortar for 30 mins. The uniformity ofdistribution of active ingredient and the in-vitro aerosol performanceswere determined as previously described. The results are reported inTable 7.

TABLE 7 Uniformity of distribution and in-vitro aerosol performancesSpherolac 100 Spherolac 100 Spherolac 100 Pharmatose 325M (63-90 μm)(90-150 μm) (150-250 μm) (30-100 μm) Content uniformity Mean (μg) 11.8911.81 12.98 11.90 RSD (%) 3.88 2.17 9.03 10.10 Shot weight Mean (mg)25.28 25.23 22.02 22.40 RSD (%) 7.73 3.39 6.93 22.00 Emitted dose (μg)11.10 10.30 8.50 7.80 FPD (μg) 1.40 0.70 0.60 1.20 FPF (%) 12.6 6.8 7.115.4

The results indicate that, upon preparation of ordered mixturescontaining formoterol fumarate as active ingredient according to theteaching of the prior art, the performance of the formulations are verypoor.

EXAMPLE 5 Powder Formulations Containing Different Amounts of FineLactose Particles.

Carrier A—α-Lactose monohydrate Spherolac 100 (90-150 μm) and Sorbolac400 with a particle size below 30 μm (d(v, 0.5) of about 10 μm) in theratio 95:5 percent by weight were mixed in a mortar for 15 mins.

Carrier B—α-Lactose monohydrate Spherolac 100 (90-150 μm) and micronisedlactose (particle size below 5 μm) in the ratio 95:5 w/w were mixed in amortar for 15 mins. Carrier C—α-Lactose monohydrate Spherolac 100(150-250 μm) and Sorbolac 400 with a particle size below 30 μm (d(v,0.5) of about 10 μm) in the ratio 95:5% by weight were mixed in a mortarfor 30 mins.

Carrier D—α-Lactose monohydrate Spherolac 100 (150-250 μm) and Sorbolac400 particle size below 30 μm (d(v, 0.5) of about 10 μm) in the ratio90:10% by weight were mixed in a mortar for 30 mins.

In the case of all the formulations tested, the carriers were mixed withformoterol fumarate in mortar for 15 mins to obtain a ratio of 12 μm ofactive to 25 mg of carrier.

The results in terms of content uniformity and in-vitro aerosolperformances are reported in Table 8.

TABLE 8 Content uniformity and in-vitro aerosol performances Carrier ACarrier B Carrier C Carrier D Content uniformity Mean (μg) 10.96 10.5011.86 — RSD (%) 1.80 15.01 7.10 — Shot weight Mean (mg) 23.46 25.29 25.719.53 RSD (%) 51.43 4.19 3.77 32.02 Emitted dose (μg) 10.40 9.5 10.15.92 FPD (μg) 1.60 2.3 2.3 1.30 FPF (%) 15.8 24.4 22.68 21.6

The results indicate that the performance of such formulations under thetest conditions are very poor.

EXAMPLE 6 “Hard-pellet Formulation Containing Coarse Lactose (PrismaLac40 Fraction below 355 μm) and fine Lactose”

α-Lactose monohydrate PrismaLac 40 with a particle size below 355 μm andSorbolac 400 with a particle size below 30 μm (d(v, 0.5) of about 10 μm)in the ratio 60:40% by weight were first manually agitated for 10 minsto promote aggregation and then blended in a Turbula mixer for 30 minsat 42 rpm. The spheronised particles were mixed with formoterol fumaratein a Turbula mixer for 30 mins at 42 rpm to obtain a ratio of 12 μg ofactive to 15 mg of carrier.

The results in terms of uniformity of distribution of active ingredientand in-vitro aerosol performances are reported in Table 9.

TABLE 9 Uniformity of distribution of active ingredient and in-vitroaerosol performances Spheronised particles Content uniformity Mean (μg)11.90 RD (%) 18.46 Shot weight Mean (mg) 18.10 RSD (%) 6.80 Emitted dose(μg) 11.10 FPD μg) 2.10 FPF (%) 18.9

The formulation without magnesium stearate thus has poor performanceunder the test conditions.

EXAMPLE 7 Effect of the Addition of Magnesium Stearate by Simple Mixing

Formulation A—α-Lactose monohydrate Pharmatose 325M (30-100 μm) andmagnesium stearate in the ratio 99.75:0.25% by weight were blended in aTurbula mixer for 2 hours at 42 rpm. The blend was mixed with formoterolfumarate in a Turbula mixer for 30 mins at 42 rpm to obtain a ratio of12 μg of active to 25 mg of carrier.Formulation B—as reported above but α-Lactose monohydrate SpheroLac 100(90-150 μm) instead of Pharmatose 325M.Formulation C—α-Lactose monohydrate PrismaLac 40 (with a particle sizebelow 355 μm) and micronised lactose with a particle size below 5 μm inthe ratio 40:60% by weight were mixed in a Turbula mixer for 60 mins at42 rpm 99.75% by weight of the resulting blend and 0.25% by weight ofmagnesium stearate were mixed in a Turbula mixer for 60 mins at 42 rpm.The resulting blend was finally mixed with formoterol fumarate in aTurbula mixer for 30 mins at 42 rpm to obtain a ratio of 12 μg of activeto 15 mg of carrier.Formulation D—Sorbolac 400 with a particle size below 30 μm (d(v, 0.5)of about 10 μm) and magnesium stearate in the ratio 98:2% by weight weremixed in a high shear mixer for 120 mins (blend A). 85% by weightα-lactose monohydrate CapsuLac (212-355 μm) and 15% by weight of blend Awere mixed in Turbula for 2 hours at 42 rpm (blend B); the amount ofmagnesium stearate in the final formulation is 0.3% by weight.Micronised formoterol fumarate was placed on the top of blend B andmixed in a Turbula mixer for 10 mins at 42 rpm to obtain a ratio of 12μg of active to 20 mg of carrier.Formulation E—Micronized lactose with a particle size below 10 μm (d(v,0.5) of about 3 μm) and magnesium stearate in the ratio 98:2% by weightwere mixed in a Sigma Blade mixer for 60 mins (blend A). 85% by weightof α-lactose monohydrate CapsuLac (212-355 μm) and 15% by weight ofblend A were mixed in Turbula for 2 hours at 42 rpm (blend B); theamount of magnesium stearate in the final formulation is 0.3% by weight.Micronised formoterol fumarate was placed on the top of blend B andmixed in a Turbula mixer for 10 mins at 42 rpm to obtain a ratio of 12μg of active to 20 mg of carrier.

The results in terms of uniformity of distribution of active ingredientand in-vitro aerosol performances are reported in Table 10.

TABLE 10 Uniformity of distribution of active ingredient and in-vitroaerosol performances Formula- Formula- Formula- Formula- Formula- tionsA tions B tions C tions D tions E Content uniformity Mean (μg) 7.9610.50 9.10 10.68 11.32 RSD (%) 2.16 8.30 24.90 2.80 3.0 Shot weight Mean(μg) 24.10 26.50 12.50 22.07 21.87 RSD (%) 34.60 8.20 15.30 2.50 4.0Emitted dose 6.10 7.60 9.60 8.60 9.93 (μg) FPD (μg) 0.60 0.90 1.60 3.384.80 FPF (%) 9.8 11.8 16.7 39.3 48.37The formulations where magnesium stearate is added, by simple mixing, tothe lactose (formulations A-B) and without the presence of added fineexcipient show very poor performance.

Formulations where magnesium stearate is added by a high energy mixingto a small amount of fine lactose (blend A of the formulations D and E)show a significant increase in performance. In addition, the particlesize of the fine lactose used has a significant effect on thedeaggregation properties of the final formulation; in fact, formulationE prepared using a micronized lactose shows a significant improvedperformance compared with formulation D.

EXAMPLE 8 Effect of the Amount of Micronized Pre-blend in the FinalFormulation

α-Lactose monohydrate SpheroLac 100 (Meggle EP D30) with a startingparticle size of 50 to 400 μm (d(v, 0.5) of about 170 μm and magnesiumstearate with a starting particle size of 3 to 35 μm (d(v, 0.5) of about10 μm) in the ratio 98:2% by weight were co-milled in a jet millapparatus (blend A) Different ratios of α-lactose monohydrate Capsulac(212-355 μm) and blend A were placed in a stainless steel container andmixed in a Turbula mixer for four hours at 32 rpm (blends B)

Micronised formoterol fumarate was placed on the top of blends B andmixed in a Turbula mixer for 30 mins at 32 rpm to obtain a ratio of 12μg of active to 20 mg total mixture. The amount of magnesium stearate inthe final formulation ranges between 0.05 and 0.6% by weight.

The results in terms of uniformity of distribution of active ingredientand in-vitro aerosol performances are reported in Table 11.

TABLE 11 Uniformity of distribution of active ingredient and in-vivoaerosol performance Ratio Ratio Ratio Ratio Ratio Ratio 97.5:2.5 95:592.5:7.5 90:10 80:20 70:30 Content uniformity Mean (g) 11.29 12.25 11.5311.93 11.96 12.00 RSD (%) 3.8 5.7 1.5 2.5 2.0 2.0 Shot weight Mean (mg)19.27 20.26 20.38 21.05 22.39 22.48 RSD (%) 4.7 3.3 3.2 4.3 3.5 3.7Emitted dose (μg) 10.58 9.20 10.65 9.18 9.63 9.88 FPD (μg) 4.18 5.106.78 5.9 5.33 5.28 FPF (%) 39.4 55.4 63.6 64.3 55.3 53.4The results indicate that the performances of all the formulations aregood.

EXAMPLE 9 Formulation Containing Lactose 90-150 μm, a MicronizedPre-blend Lactose/Magnesium Stearate Mixture Obtained by Jet Milling andFormoterol as Active Ingredient

α-Lactose monohydrate SpheroLac 100 (Meggle EP D30) with a startingparticle size of 50 to 400 μm (d(v, 0.5) of about 170 μm and magnesiumstearate with a starting particle size of 3 to 35 μm (d(v, 0.5) of about1 μm) in the ratio 98:2% by weight were co-milled in a jet millapparatus (blend A).

92.5% by weight of α-lactose monohydrate Spherolac with a startingparticle size of 90 to 150 μm (d(v, 0.5 of about 145 μm) and 7.5% byweight of blend A were placed in a stainless steel container and mixedin a Turbula mixer for four hours at 32 rpm (blends B)

Micronised formoterol fumarate was placed on the top of blends B andmixed in a Turbula mixer for 30 mins at 32 rpm to obtain a ratio of 12μg of active to 20 mg total mixture. The amount of magnesium stearate inthe final formulation is 0.15% by weight.

The results in terms of uniformity of distribution of active ingredientand in-vitro aerosol performances are reported in Table 12.

TABLE 12 Uniformity of distribution of active ingredient and in-vitroaerosol performances Content uniformity Mean (μg) 11.75 RSD (%) 1.50Shot weight Mean (mg) — RSD (%) — Emitted dose (μg) — FPD (μg) 5.71 FPF(%) 45.2

From the reported results, it can be appreciated that, as long as thefraction of fine particles is less than 10% by weight, the performancesof a formulation containing standard lactose as coarse carrier fractionand a fine particle fraction excipient obtained either by co-milling orby co-mixing, are very good.

EXAMPLE 10 Effect of the Time of Mixing

Different blends were prepared by co-mixing CapsuLac 212-355 μm,micronized lactose with a particle size below 10 μm (d(v, 0.5) of about3 μm) and magnesium stearate in the ratio 89.8:10:0.2% by weight, in aTurbula mixer (32 rpm) at increasing mixing time (1, 2 and 4 hours).

Micronised formoterol fumarate was placed on the top of each blend andmixed in a Turbula mixer for 30 mins at 32 rpm to obtain a ratio of 12μg of active to 20 mg total mixture.

The results in terms of fine particle fraction (FPF) are reported inTable 13.

TABLE 13 Effect of the mixing time on FPF Time of mixing Fine particlefraction (%) 1 hour  21.0 2 hours 34.2 4 hours 40.5

The results indicate that good performances in terms of fine particlefraction are achieved after mixing for at least two hours.

EXAMPLE 11

20 g of Microfine lactose (Burculo-MMAD about 8 μm) and 0.4 g ofL-leucine (Ajinomoto) were combined and placed in a stainless steel ballmill, filled with stainless steel balls of varying diameter toapproximately 50% of the mill volume. The mill was rotated atapproximately 60 RPM for about 120 minutes. The milled material (MMADabout 5 μm) was then recovered from the mill and from the surface of theballs, and is referred to below as the fines.

8 g of sieved Prismalac lactose was weighed into a glass vessel.Prismalac (trade mark) lactose is sold in the UK by Meggle for use intablet manufacture. The lactose, as purchased, had been sieved on astack of sieves in order to recover the sieve fraction passing through a600 μm mesh sieve, but not passing through a 355 μm mesh sieve. Thatfraction is referred to below as 355-600 Prismalac and has a mean tappeddensity of 0.49 g/cm³ and a bulk density as measured by mercuryintrusion porosimetry of 0.47 g/cm³.

1 g of the fines obtained as described above, and 1 g of micronisedsalbutamol sulphate (MMAD-2 μm) was added to the 355-600 Prismalac inthe glass vessel. The glass vessel was sealed and the vessel located ina “Turbula” tumbling blender. The vessel and contents were tumbled forapproximately 30 minutes at a speed of 42 RPM.

The formulation so obtained was loaded into size 3 gelatin capsules at20 mg per capsule. The loaded capsules were rested for a period of 24hours. Three capsules were then fired sequentially into a Twin StageImpinger at a flow rate of 60 litres per minutes, with a modified stage1 jet of 12.5 mm internal diameter, which was estimated to produce acut-off diameter of 5.4 μm. The operation of the Twin Stage Impinger isdescribed in WO95/11666.

Modification of a conventional Twin Stage Impinger, including the use ofmodified stage 1 jets, is described by Halworth and Westmoreland (J.Pharm. Pharmacol. 1987, 39:966-972).

TABLE 14 Comparison Comparison Example 1 1 2 355-600 Prismalac    8 g  80% 8 g   4 g lactose Salbutamol sulphate    1 g   10% 1 g 0.5 gMicrofine lactose 0.9804 g 9.804% — 0.5 g Leucine 0.0196 g 0.196% — Fineparticle 50% 10% 40% fraction

The composition of the formulation is summarised in Table 14 above.

As shown in Table 14, the fine particle fraction is improved in thepresence of added fine lactose (Comparison 2) as compared with aformulation which contains no added fine lactose (Comparison 1). Thebest performance is obtained from the formulation according to theinvention, containing leucine as well as fine lactose. On omission ofthe Prismalac from the ingredients of Example 11, the formulation wasfound to have very poor flow properties, preventing reliable andreproducible metering. As a result, the fine particle fraction was foundto be very variable.

EXAMPLE 12

Example 11 was repeated using Prismalac lactose which had been sieved,the sieve fractions of 212 to 355 μm (with mean tapped density 0.65g/cm³ and a bulk density as measured by mercury instrusion porosimetryof 0.57 g/cm³) being recovered and used instead of the 355-600 Prismalaclactose used in Example 11. Once again, a fine particle fraction ofabout 50% was obtained.

EXAMPLE 13

Example 11 was repeated replacing the leucine by one of the following:lecithin, stearylamine, magnesium stearate, and sodium stearyl fumarate.

The results are summarised in Table 15.

TABLE 15 Additive Fine particle fraction Lecithin 50% Stearylamine 50%Purified phosphatidyl cholines 35% Sodium stearyl fumarate 40%

EXAMPLE 14

95 g of Microfine lactose (Borculo) was placed in a ceramic millingvessel (manufactured by the Pascall Engineering Company). 5 g ofadditive material (L-leucine) and the ceramic milling balls were added.The ball mill was tumbled at 60 rpm for 5 hours. The powder wasrecovered by sieving to remove the milling balls.

0.9 g of the composite excipient particles so obtained containing 5%l-leucine in Microfine lactose was blended with 0.6 g of budesonide byhand in a mortar. This blending could also be performed, for example, ina high shear blender, or in a ball mill or in a centrifugal mill. 20parts by weight sample of this powder were blended with 80 parts byweight of a coarse carrier lactose (sieve-fractionated Prismalac—355 to600 μm fraction) by tumbling. The powder was fired from a Cyclohaler ata flow rate of 60 l/minute in a multi-stage liquid impinger. The fineparticle fraction (<approx. 5 μm) was 45%.

EXAMPLE 15

98 g of Microfine (MMAD approximately 8 μm) lactose (manufactured byBorculo) was placed-in a stainless steel milling vessel. 300 g ofstainless steel milling balls varying from 10 to 3 mm diameter wereadded. 2 g of lecithin was added and the vessel was located in a RetschS100 Centrifugal Mill. The powder was milled for 30 minutes at 580 rpmand was then sieved to remove the milling balls.

1 g of salbutamol sulphate was added to 1 g of the composite excipientparticles so obtained containing 2% lecithin, and to 8 g ofsieve-fractionated Prismalac lactose (355 to 600 μm fraction). Themixture was tumbled for 30 minutes at 42 rpm. The resulting powder wasfired from a Cyclohaler at a flow rate of 60 litres per minute into atwin-stage impinger, giving a fine particle fraction (<approx. 5microns) of about 44%. A similar example with a 2% leucine precursorgave a fine particle fraction (<approx. 5 μm) of 52%.

Other additive materials that may be used instead of lecithin to formcomposite excipient particles as described above are: magnesiumstearate, calcium stearate, sodium stearate, lithium stearate, stearicacid, stearylamine, soya lecithin, sodium stearyl fumarate, 1-leucine,1-iso-leucine, oleic acid, starch, diphosphatidyl choline, behenic acid,glyceryl behenate, and sodium benzoate. Pharmaceutically acceptablefatty acids and derivatives, waxes and oils may also be used.

EXAMPLE 16

10 g of Microfine lactose (Borculo) was combined with 1 g of magnesiumstearate and 10 cm³ cyclohexane. 50 g of 5 mm balls were added and themixture was milled for 90 minutes. The powder was recovered by leavingthe paste in a fume hood overnight to evaporate the cyclohexane and thenball milling for 1 minute.

0.5 g of salbutamol sulphate was added to 0.5 g of the compositeexcipient particles so obtained containing magnesium stearate, and to 4g of sieve-fractionated Prismalac lactose (355-600 μm fraction). Thiswas tumbled for 30 minutes at 62 rpm. The resulting powder was firedfrom a Cyclohaler at a flow rate of 60 litres per minute into atwin-stage impinger, giving a fine particle fraction (<approx. 5 μm) of57%. The experiment was repeated using composite excipient particlescontaining 20% magnesium stearate and similar results were obtained.

EXAMPLE 17

10 g of Microfine lactose (Borculo) was combined with 1 g of leucine and10 cm³ cyclohexane. 50 g of 5 mm balls were added and the mixture wasmilled for 90 minutes. The powder was recovered by leaving the paste ina fume hood overnight to evaporate the cyclohexane and then ball millingfor 1 minute.

0.5 g of salbutamol sulphate, 0.25 g of composite excipient particlesmade as described in Example 16 containing magnesium stearate, 0.25 g ofcomposite excipient particles made as described above containingleucine, and 4 g of sieve-fractionated Prismalac (355-600 μm fraction)were all combined. The mixture was tumbled for 30 minutes at 62 rpm. Theresulting powder was fired from a Cyclohaler at a flow rate of 60 litresper minute into a twin-stage impinger, giving a fine particle fraction(<approx. 5 μm) of ˜65%.

EXAMPLE 18

10 g of Microfine lactose (Borculo) was combined with 1 g of lecithinand 10 cm³ cyclohexane. 50 g of 5 mm balls were added and the mixturewas milled for 90 minutes. The powder was recovered by leaving the pastein a fume hood overnight to evaporate the cyclohexane and then ballmilling for 1 minute.

0.5 g of salbutamol sulphate was added to 0.25 g of the compositeexcipient particles so obtained containing lecithin, 0.25 g of compositeexcipient particles made as described in Example 17 containing leucine,and 4 g of sieve-fractionated Prismalac lactose (355-600 μm fraction).The mixture was tumbled for 30 minutes at 62 rpm. The resulting powderwas fired from a Cyclohaler at a flow rate of 60 litres per minute intoa Twin-Stage Impinger, giving a fine particle fraction (<approx. 5 μm)of 68%.

EXAMPLE 19

95 g Sorbolac 400 (Meggle) were combined with 5 g of magnesium stearateand 50 ml dichloromethane and milled in a Retsch S100 centrifugal millwith 620 g of 5 mm stainless steel balls in a stainless steel vessel for90 minutes at 500 rpm. The powder was recovered after evaporation of thedichloromethane by briefly milling (1 minute) and subsequent sieving. 10g of the composite excipient/additive particles so obtained were addedto 89.5 g of sieve fractionated Prismalac lactose (355-600 μm fraction).The mixture was tumbled for 30 minutes at 60 rpm, then 0.5 g budesonidewas added and tumbling continued for a further 30 minutes at 60 rpm. Thepowder was fired from a Cyclohaler at 60 l/minute into a Twin-StageImpinger, and gave a fine particle fraction (<5 approx. μm) of about80%.

EXAMPLE 20

-   (a) A pre-blend was made by milling an additive material and    microfine lactose (<20 micron) together in a ball mill. Then 1 g of    the pre-blend, 1 g of salbutamol sulphate and 8 g of coarse lactose    (Prismalac 355-600) were mixed together in a glass vessel in a    Turbula mixer at 42 rpm to create the final formulation. Size 2    capsules were filled with 20 mg of the formulation. For each test, 3    capsules were fired into a ‘rapid TSI’ from a Cyclohaler giving a    total delivered dose of 6 mg of salbultamol sulphate per test. The    additive material was selected from lithium stearate, calcium    stearate, magnesium stearate, sodium stearate, sodium stearyl    fumarate, leucine, lecithin and stearylamine.-   (b) The method of (a) above was repeated using leucine, except that    the pre-blend was mixed with the coarse lactose in a glass vessel    shaken by hand.

The “rapid TSI” is a modified methodology based on a conventional TSI.In the rapid TSI the second stage of the impinger is replaced by a glassfibre filter (Gelman A/E, 76 mm). This enables the fine particlefraction of the formulation (i.e. particles with an MMAD< approx. 5 um)to be collected on a filter for analysis. Analysis was conducted bysonicating the filter in a 0.06M NaOH solution and analysed at 295 nm ona UV spectrophotomer (Spectronic 601). The fine particle fractioncorresponds substantially to the respirable fraction of the formulation.

Further details of the formulations and the % fine particle fractionestimated using the “rapid TSI” method described above are given inTable 16 below, in which SaSO₄ refers to salbutamol sulphate.

Segregation has not been observed in the above formulations, even thosecomprising 10 and 20% magnesium stearate (i.e. up to 2% in the finalcomposition).

The above processes have been applied to a variety of active materials.When the active material is a protein, the milling may be preceded bylyophilisation (freeze drying) of the protein either pure or incombination with an additive material and/or a polymeric stabiliser. Thefreeze drying may make the protein more brittle and more easily milled.The milling may need to be conducted under cryogenic (cold) conditionsto increase the brittleness of the material.

TABLE 16 Additive % AM in % AM in Mass Pre- Material pre- formula- (mg)Estimated blend mill (“AM”) blend tion SaS04 % FPF method Lithium St 20.2 2.549 42 30 mins 2.763 46 Calcium St 2 0.2 2.721 45  1 hr 2.633 44Magnesium St 2 0.2 2.108 35  1 hr 2.336 39 Sodium St 2 0.2 3.218 54 30mins 3.153 53 Sodium 2 0.2 2.261 38 30 mins stearyl 2.113 35 FumarateLeucine 2 0.2 2.429 40  2 hrs 2.066 34 Leucine 2 0.2 2.136 36  2 hrs [12(b)] 2.600 43 Leucine 5 0.5 2.782 46 30 mins 3.000 50 Leucine 5 0.52.772 46 2.921 49  5 hrs Magnesium St 5 0.5 2.438 41 30 mins 2.721 45Lecithin 2 0.2 3.014 50 30 mins 2.884 48 Stearylamine 2 0.2 2.847 47 30mins 3.037 51

EXAMPLE 21

10 g of the composite excipient particles containing 5% magnesiumstearate obtained in accordance with Example 19 were mixed with 89.5 gcoarse lactose (Prismalac; 355-600 μm fraction) in a Turbula mixer for30 minutes. 0.5 g micronised dihydroergotamine mesylate was added andmixing continued in the Turbula for a further 30 minutes. The powder wasfired from a Cyclohaler into a MultiStage Liquid Impinger (Apparatus C,European Pharmacopoeia, Method 5.2.9.18, Supplement 2000), and gave afine particle fraction (< approx. 5 μ) of about 60%.

EXAMPLE 22

Composite excipient particles were manufactured by milling 95 g finelactose (Sorbolac 400-Meggle) with 5 g magnesium stearate and 50 mldichloromethane in a Retsch 5100 centrifugal mill with 620 g of 5 mmstainless steel balls in a stainless steel vessel for 90 minutes at 500rpm. The powder was recovered after evaporation of the dichloromethaneby briefly milling (1 minute) and subsequent sieving. 10 g of thecomposite excipient/additive particles so obtained were added to 89.5 gof sieve fractionated Prismalac Lactose (355-600 μm fraction). Themixture was tumbled in a Turbula mixer for 30 minutes at 60 rpm, then0.5 g fentanyl citrate was added and tumbling continued for a further 30minutes at 60 rpm. The powder so obtained was fired from a Cyclohaler at60 l/min into a Twin-Stage Impinger, and gave a fine particle fraction(< approx. 5 μm) of about 50%.

EXAMPLE 23

Various formulations, each combining 89.5 g Prismalac 10 g compositeexcipient particles and 0.5 g budesonide according to the method ofExample 19. Their flowabilities were then measured using a FLODEX (trademark) tester, made by Hanson Research. The FLODEX provides an index,over a scale of 4 to 40 mm, of flowability of powders. Analysis wasconducted by placing 50 g of formulation into the holding chamber of theFLODEX via a funnel, allowing the formulation to stand for 1 minutes,and then releasing the trap door of the FLODEX to open an orifice at thebase of the holding chamber. Orifice diameters of 4 to 34 mm were usedto measure the index of flowability. The flowability of a givenformulation is determined as the smallest orifice diameter through whichflow of the formulation is smooth. The results are shown in Table 17.Comparison data is given for a formulation made by mixing for 30 minutesin a Turbula mixer 45 g Pharmatose 325M lactose (a lactose used incertain conventional formulations) and 5 g microfine lactose.

TABLE 17 Flowa- Carrier particles Composite particles bility Prismalac355-600 Leucine:Sorbolac 400 1:9  <4 mm Prismalac 355-600Leucine:Sorbolac 400 1:9  <4 mm Prismalac 355-600 Magnesium stearate:Sorbolac 400 1:19  <4 mm Prismalac 355-600 Magnesium stearate: microfine <4 mm lactose 1:19 Pharmatose 325M Microfine lactose >34 mm

The results in Table 17 illustrate the excellent flowability offomulations using fissured lactose.

Comparison Example 1

99.5 g of sieve-fractionated Prismalac (355-600 μm fraction) was tumbledwith 0.5 g budesonide for 30 minutes at 60 rpm. The powder, fired from aCyclohaler at 90 litres per minute into a Multi-Stage Liquid Impingergave a fine particle fraction (<5 μm) of about 30%.

1. A powder for use in a dry powder inhaler, the powder comprising: i) afraction of fine particles prepared as a pre-blend mixture byco-micronising, co-milling or high energy mixing of a physiologicallyacceptable excipient and an additive, the mixture having a mean particlesize of less than 35 μm and comprising composite excipient particles inwhich the additive material at least partially coats the surfaces of theexcipient particles; ii) a fraction of coarse particles constituted of aphysiologically acceptable carrier having a particle size of at least 90μm, and having a fissured surface, the coarse carrier particles having:(a) a tapped density not exceeding 0.7 g/cm³; (b) a bulk density asmeasured by mercury porosimetry not exceeding 0.6 g/cm³; (c) a totalintrusion volume of at least 0.8 cm³/g; (d) a fissure index of at least1.25, when measured using a test as described in the description; or (e)a mean rugosity coefficient of at least 1.25, when measured using a testas described in the description; wherein the surfaces of the coarsecarrier particles are at least partially coated with additive material;and iii) at least one active ingredient; said mixture (i) being composedof up to 99% by weight of particles of the excipient and at least 1% byweight of additive and the ratio between the fine excipient particlesand the coarse carrier particles being between 1:99 and 40:60% byweight.
 2. A powder according to claim 1, which is in the form of ‘hardpellets’.
 3. A powder according to claim 1, wherein the mixture (i) iscomposed of from 90 to 99% by weight of the excipient particles and from1 to 10% by weight additive.
 4. A powder according to claim 1, whereinthe ratio between the fraction with a fine particle size and the coarseparticle fraction is at least 10:90.
 5. A powder according to claim 4,wherein the ratio between the fraction with a fine particle size and thecoarse particle fraction is comprised between 15:85 and 30:70% byweight.
 6. A powder according to claim 1, wherein the additive particlespartially coat the surface of the fine excipient particles and/or thecoarse, carrier particles.
 7. A powder according to claim 1, wherein thecoarse particle fraction is constituted of a physiologically acceptableexcipient which has a particle size of 100 to 400 μm.
 8. A powderaccording to any one of claims 1 to 4, in which the particle size of themixture (i) is less than 15 μm.
 9. A powder according to claim 1, inwhich the fraction with a fine particle size is composed of 98% byweight of the physiologically acceptable excipient and 2% by weight ofthe additive and the ratio between the fraction with a fine particlesize and the coarse particle fraction is 10:90% by weight.
 10. A powderaccording to claim 1, wherein the additive is selected from the classesof lubricants, antiadherents or glidants.
 11. A powder according toclaim 1, wherein the additive is magnesium stearate.
 12. A powderaccording to claim 1, wherein the physiological acceptable excipient isone or more crystalline sugars.
 13. A powder according to claim 1,wherein the physiological acceptable excipient is α-lactose monohydrate.14. A powder according to claim 1, wherein the active ingredient has aparticle size less than 10 μm.
 15. A powder according to claim 1,wherein the additive is magnesium stearate and the active ingredient(s)is (are) not selected from budesonide and its epimers, formoterol,TA2005 and its stereoisomers, salts thereof, and combinations thereof.16. A powder according claim 1, comprising more than 5%, by weight,based on the total weight of the formulation, of particles ofaerodynamic diameter less than 20 μm, the formulation having aflowability index of 12 mm or less.
 17. A process for making a powderaccording to claim 1, said process including the steps of: a)co-micronising the excipient particles and the additive particles so asto significantly reduce their particle size; b) spheronising by mixingthe resulting mixture with the coarse carrier particles such thatmixture particles adhere to the surface of the coarse carrier particle;c) adding by mixing the active particles to the spheronised particles.18. A process according to claim 17 wherein step a) is carried out bymilling.
 19. A process for making a powder according to claim 1, saidprocess including the steps of: a) mixing in a Turbula or high-energymixer the excipient particles and the additive particles wherein theexcipient particles have a starting particle size less than 35 μm; b)spheronising by mixing the resulting mixture with the coarse carrierparticles such that mixture particles adhere to the surface of thecoarse carrier particles; c) adding by mixing the active particles tothe spheronised particles.
 20. A process according to claim 19 whereinthe excipient particles of step a) have a starting particle size of lessthan 15 μm.
 21. A process according to claim 17, wherein the additiveparticles at least partially coat the surface of the excipientparticles.
 22. The powder according to claim 16, comprising more than10% by weight, based on the total weight of the formulation, ofparticles of aerodynamic diameter less than 20 μm, the formulationhaving a flowability index of 12 mm or less.
 23. The process accordingto claim 18, wherein a jet mill is used for said milling.
 24. The powderaccording to claim 1, wherein said coarse particles have a rugous shape.25. The powder of claim 1, wherein the coarse particles comprisescrystalline sugars.
 26. The powder of claim 1, wherein the additivematerial particles at least partially coat both the surface of thephysiologically acceptable excipient and the coarse particlesconstituted of a physiologically acceptable carrier.
 27. The powder ofclaim 1, wherein the coarse carrier particles have: (a) a tapped densitynot exceeding 0.7 g/cm³; (b) a bulk density as measured by mercuryporosimetry not exceeding 0.6 g/cm³; (c) a total intrusion volume of atleast 0.8 cm³/g; (d) a fissure index of at least 1.25, when measuredusing a test as described in the description; and (e) a mean rugositycoefficient of at least 1.25, when measured using a test as described inthe description.
 28. A powder according to claim 14, wherein the activeingredient has a particle size less than 6 μm.